CLINICAL TRIAL SPOTLIGHT

Multiple Sclerosis Drug May Be the Next Dry AMD Intervention

Can a drug that has helped MS patients have an impact on nonexudative AMD?

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

In the past few months, clinical trials have begun enrollment in the United States and Israel to test the safety and efficacy of glatiramer acetate (GlA; Copaxone, Teva Pharmaceuticals) for the treatment of dry age-related macular degeneration (AMD). GlA is currently approved by the Food & Drug Administration (FDA) only for the treatment of multiple sclerosis. Retinal Physician spoke to Gennady Landa, MD, from the departments of ophthalmology at Kaplan Medical Center in Rehovot, Israel, and the New York Eye and Ear Infirmary, about how such a drug could be helpful for dry AMD patients.

"The mechanism of action of Copaxone and its impact on AMD is quite complex," Dr. Landa began. "We know that, in most neurodegenerative diseases, a local immune response takes place. Microglia cells, a type of immune resident cell, play a crucial role in inflammation and in local immune response. Activated microglia cells are needed for tissue defense," Dr. Landa continued. "When resting microglia are activated by innate immunity activators, they are transformed to a phagocytic phenotype that is characterized by production of various inflammatory mediators. These activated microglia cells become cytotoxic and can kill and remove microorganisms."

When microglia cells are activated by adaptive immunity mediators, such as T-cell-derived cytokines, a neuroprotective phenotype of microglia develops, Dr. Landa says. This phenotype enables microglia to act as antigen-presenting cells. Amyloid beta is one of the main proteins present both in drusen AMD and in the deposits of Alzheimer's disease (AD). There is a common inflammatory pathway for both AMD and AD. An accumulation of extracellular amyloid in AD plaques or drusen triggers a local toxic chronic inflammatory response where cytotoxic microglia produce neurotoxins, causing neurodegeneration. Accumulation of these deposits is associated with loss of photoreceptors and deterioration of macular function, analogous to neuronal loss and cognitive decline in AD.

"These implications made us think that, in AD and in AMD, an immune response should be modulated rather than suppressed and that 'the perfect microglia/macrophages' could remove plaque/drusen without cytotoxicity and could support repair," Dr. Landa said. "Vaccination with GlA could be used for boosting the level of T cells needed to shape microglia/monocytes in AD and perhaps in AMD. Such a vaccination via interleukin (IL)-4, will render the local immune response the ability to fight off the adverse conditions created by the plaques or drusen.

Glatiramer acetate has been tested on AD-transgenic mice by treating them in a protocol in which an immune response was induced. Five weeks after the first GlA-injection, brain cryosections from the mice showed marked reduction in amyloid beta plaques in the brains of GlA-vaccinated mice in contrast to untreated mice. "Further experiments showed IL-4 induces not only neuroprotective phenotype of microglia but also counteracts the detrimental effect of amyloid beta on microglia cells," Dr. Landa said. "In light of the similarity in the deposition and the inflammatory response between AD and AMD, our next aim was to investigate whether the effect of GlA on drusen in dry AMD was similar to that on deposits of other age-related chronic neurodegenerative diseases such as AD."

Currently, there are no phased studies of GlA for dry AMD under way. Asked why the current emphasis in clinical trials was on dry AMD and not wet AMD as well, Dr. Landa responded, "The preliminary results show that GlA might have a potential to reduce the mass of drusen in dry AMD patients. The subsequent neuroprotective effect in arresting the progression in wet AMD is also currently under investigation." Asked when phased studies of GlA for dry AMD would begin, Dr. Landa said, "We are planning to initiate phased studies as soon as we get statistically significant results based on these 2 preliminary studies." RP